#2021BSQ-NOV Q31
These are more clearly seen in type I DM.
In type 2 DM, vascular and tubulointerstitial changes predominate.
Mesangial proliferation -> further proliferation + matrix deposition -> PAS positive kimmelstiel-Wilson bodies.
[!INFO]
This 'neat' sequence is best observed in type 1 DM. It's more complicated in Type 2
[!INFO]
Glomerulus from a type 1 diabetic (T1DM) patient with diffuse (long thick arrow) and nodular (short thick arrow) mesangial expansion and afferent (double thin arrows) and efferent (single thin arrow) arteriolar hyalinosis. Source
Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive
[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion
| Hypothalamic diseases | Pituitary diseases |
|---|---|
| Mass lesions – Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc) | Mass lesions – Pituitary adenomas, other benign tumors, cysts |
| Radiation – For CNS and nasopharyngeal malignancies | Pituitary surgery |
| Infiltrative lesions – Sarcoidosis, Langerhans cell histiocytosis | Pituitary radiation |
| Infections – Tuberculous meningitis | Infiltrative lesions – Hypophysitis, hemochromatosis |
| Other – Traumatic brain injury, stroke | Infection/abscess |
| Infarction – Sheehan syndrome | |
| Apoplexy | |
| Genetic mutations | |
| Empty sella |

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]
| Hormone Type | Site of secretion | Mechanism of action | Receptor Sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| Peptide | Somatotroph cells of Anterior pituitary | Mainly acts on the liver to stimulate IGF-1 production, Acts directly and indirectly on epiphyseal bone | cell membrane receptor (esp. on hepatocytes). Receptor defects cause Laron dwarfism | Pulsatile (10 pulses per day, 90 minutes each -easy to miss in a spot sample) | ||
Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin
Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.
[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity
[!Tip] Mnemonic: GH affects all macromolecules - makes things grow
- Lipids -> increase lipolysis
- Proteins -> Increased protein synthesis
- Glucose -> Promotes insulin resistance
- Electrolytes -> Phosphate, salt and water retention
- Bone -> Epiphyseal bone growth
In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)
Commonest cause in adults: somatotroph adenoma
Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)
Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]
As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:
[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases
^da9653
[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia
Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.
- Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
- Other effects include
- a lesser stimulation of intestinal phosphate absorption
- direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
- regulation of osteoblast function, and
- permissively allowing PTH-induced osteoclast activation and bone resorption.
- Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.
^83ab8b
The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:
Activated vitamin D levels are elevated in #pregnancy
The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.
| type | Site | Mechanism | Receptor sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| peptide | Chief cells of parathyroid gland | ↑ osteoclast bone resorption, ↑ intestinal absorption, ↑ synthesis of D3, ↑ renal rubular resorption, ↑ phosphate excretion | cell membrane |
^0f3395
PTH increases renal phosphate excretion and increases plasma calcium by:
Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.
[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)
Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.
PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source
#2021BSQ-NOV Q08
Indications for therapeutic used:
^070bf7
About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.
| Region | Mechanism | Percentage |
|---|---|---|
| PCT | Passive | 60% |
| TAL | 15% | |
| DCT (site of regulation) | Active | 15% |
| Collecting duct | 0% |
PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source
PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2
[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]
Causes are devided into
malignancy and primary hyperparathyroidism = 90% of cases.

Causes of Severe hypercalcaemia :
Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.
After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate
Not very common
In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures
Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype
Patients have albright phenotype BUT
All biochemistry is normal
[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 depositionTo illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia
Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.
Common in CKD
Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO
Two types of bone formation
Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:
Bone development includes
An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis
Bone deposition and resorption is influenced by both systemic and local factors.
| Systemic | Local |
|---|---|
| + PTH & calcitriol | Prostaglanding |
| GH / IGF-1 | Transforming growth factor (TGF) |
| Glucocorticoids | Bone morphogenic proteins (BMP) |
| thyroid hormones | Cytokines |
| sex hormones | (Levels of local regulators are influenced by mechanical stress, local inflammation etc.) |
More complicated than you might think
| Decrease bone turnover | Increase bone turnover |
|---|---|
| Parathyroid hormones - Intermittent administration -> Stimulates bone formation | PTH - Continous presense --> bone resorption |
| Calcitriol | If Ca and PO4 are low, high levels of Calcitriol can stimulate resorption |
| Estrogens - decrease bone turn over | glucocorticoids (glucocorticoid induced osteoporosis) |
| Calcitonin - physiologically redundant, pharmacologic doses -> onyl a transient effect of reducing bone resorption | Thyroid hormones - BOTH deposition and resorption. (bone loss can occur in hyperthyroidism) |
| TGF beta adn BMP |
Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]
Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.
[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.
T3 binds to nuclear recetpor --> Exerts effects
T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23
| System | effect |
|---|---|
| CVS | Increase cardiac ouput |
| RS | Maintains respiratory drive |
| GI | increases motility |
| Blood | Incr. 23-DPG - increased oxygen unloading |
| Muscles | Increase speed of muscle contraction |
| Carbs | Increase gluconeogen, glycolysis, sugar absorption |
| lipid | Lipolysis + increased cholesterol turnover |
| Sympathetic NS | Increases expression of beta adrenergic receptors and in heart decreases alpha receptors |
There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease
Low TSH usually means hyperthyroidism except in
High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)
Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32
Common cause of hyperthyroidism
Commoner in women - 30 - 60 years.
Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)
Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.
Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;
Disease follows a relapsing remitting course. Majority have recurrences.
Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia
Patients will usually eventually become hypothyroid.
Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.
Others causes of hyperthyroidism: 
Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.
[!TIP] C --> M: Alphabetical order
[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure
#2022BSQ Q16
Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.
| Carbimazole / methimazole | Propylthiouracil |
|---|---|
| Less severe side effects. Usually first line choice | Usually second line, except T1 of pregnancy, and thyroid storm |
| Blocks 5'-monodeiodinase, which converts peripheral T4 to T3 conversion | |
| Less frequent teratogenic effects | |
| Pruritus, rash, arthritis, urticaria, abnormal taste | Same |
| Agranulocytosis (0.1% incidence) | Same |
| Less risk of hepatic injury | Fulminant hepatic failure |
| ANCA positive vasculitis |
[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.
Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.
Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.
Thyroiditis typically causes a painful goiter.
[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic
Grand Seikos are japanese watches -> chronic ;)
| Hashimoto's | De quervain | Post partum | Drug induced | radiation | Infectious | Silent |
|---|---|---|---|---|---|---|
| chronic autoimmune - months to years | Post viral thyroiditis - days | rare, around 6 months post partum, resolves by 12 months PP | Lithium, interferons | radio-iodine therapy | rare, bacterial infection | |
| Rubbery gland | Painful, warm thyroid | |||||
| Transient hyper, then hypothyroidism | Hyper and then hypothyroidism | |||||
| risk factors: type 1 DM and previous episodes |
Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.
fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.
| Image 1 | Image 2 |
|---|---|
|  |  |
Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)
Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.
Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.
Levothyroxine (aka L thyroxine) is synthetic T4.
Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.
Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin
Lactotroph adenoma - usually very high prolactin levels.
Loss of dopaminergic inhibition
Oestrogen tends to increase prolactin levels.
Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.
Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery
Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.
Dysfunction of islet specific glucokinase can cause one type of MODY.
Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.
[!INFO] Insulin helps to coordinate between different types of fuel used by the body.
Coordination of glucose and lipid metabolism by insulin
- in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
- In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.
Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.
Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]
#2021BSQ-NOV Q07
[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.
| Transporter | Site |
|---|---|
| SGLT-1 | small intestine and renal tubules |
| SGLT-2 | renal tubules |
| GLUT 1,3 | basal glucose uptake 'everywhere' |
| GLUT 2 | beta cell glucose sensor |
| GLUT 4 | insulin mediated glucose uptake in Sk and cardiac muscle, adipocytes |
| GLUT 5 | Fructose transporter |
There are three main types of estrogen: Source
Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.
The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded
If a patients has feature of Chushing's syndrome
bedtime salivary cortisol
24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.
Low dose DST
For bedtime salivary cortisol and UFC, two abnormal tests are required.
If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.
Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)
Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.
Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.
First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.
Because of cyclical variations, testing at two different times is recommended.
ACTH < 5pg/ML = ACTH independent hypercortisolism
ACTH > 20pg/mL = ACTH dependent hypercortisolism.
ACTH dependent Hypercortisolism
A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.
Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.
[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products
Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive
[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion
| Hypothalamic diseases | Pituitary diseases |
|---|---|
| Mass lesions – Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc) | Mass lesions – Pituitary adenomas, other benign tumors, cysts |
| Radiation – For CNS and nasopharyngeal malignancies | Pituitary surgery |
| Infiltrative lesions – Sarcoidosis, Langerhans cell histiocytosis | Pituitary radiation |
| Infections – Tuberculous meningitis | Infiltrative lesions – Hypophysitis, hemochromatosis |
| Other – Traumatic brain injury, stroke | Infection/abscess |
| Infarction – Sheehan syndrome | |
| Apoplexy | |
| Genetic mutations | |
| Empty sella |

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]
| Hormone Type | Site of secretion | Mechanism of action | Receptor Sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| Peptide | Somatotroph cells of Anterior pituitary | Mainly acts on the liver to stimulate IGF-1 production, Acts directly and indirectly on epiphyseal bone | cell membrane receptor (esp. on hepatocytes). Receptor defects cause Laron dwarfism | Pulsatile (10 pulses per day, 90 minutes each -easy to miss in a spot sample) | ||
Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin
Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.
[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity
[!Tip] Mnemonic: GH affects all macromolecules - makes things grow
- Lipids -> increase lipolysis
- Proteins -> Increased protein synthesis
- Glucose -> Promotes insulin resistance
- Electrolytes -> Phosphate, salt and water retention
- Bone -> Epiphyseal bone growth
In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)
Commonest cause in adults: somatotroph adenoma
Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)
Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]
As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:
[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases
^da9653
[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia
Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.
- Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
- Other effects include
- a lesser stimulation of intestinal phosphate absorption
- direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
- regulation of osteoblast function, and
- permissively allowing PTH-induced osteoclast activation and bone resorption.
- Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.
^83ab8b
The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:
Activated vitamin D levels are elevated in #pregnancy
The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.
| type | Site | Mechanism | Receptor sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| peptide | Chief cells of parathyroid gland | ↑ osteoclast bone resorption, ↑ intestinal absorption, ↑ synthesis of D3, ↑ renal rubular resorption, ↑ phosphate excretion | cell membrane |
^0f3395
PTH increases renal phosphate excretion and increases plasma calcium by:
Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.
[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)
Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.
PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source
#2021BSQ-NOV Q08
Indications for therapeutic used:
^070bf7
About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.
| Region | Mechanism | Percentage |
|---|---|---|
| PCT | Passive | 60% |
| TAL | 15% | |
| DCT (site of regulation) | Active | 15% |
| Collecting duct | 0% |
PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source
PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2
[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]
Causes are devided into
malignancy and primary hyperparathyroidism = 90% of cases.

Causes of Severe hypercalcaemia :
Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.
After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate
Not very common
In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures
Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype
Patients have albright phenotype BUT
All biochemistry is normal
[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 depositionTo illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia
Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.
Common in CKD
Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO
Two types of bone formation
Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:
Bone development includes
An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis
Bone deposition and resorption is influenced by both systemic and local factors.
| Systemic | Local |
|---|---|
| + PTH & calcitriol | Prostaglanding |
| GH / IGF-1 | Transforming growth factor (TGF) |
| Glucocorticoids | Bone morphogenic proteins (BMP) |
| thyroid hormones | Cytokines |
| sex hormones | (Levels of local regulators are influenced by mechanical stress, local inflammation etc.) |
More complicated than you might think
| Decrease bone turnover | Increase bone turnover |
|---|---|
| Parathyroid hormones - Intermittent administration -> Stimulates bone formation | PTH - Continous presense --> bone resorption |
| Calcitriol | If Ca and PO4 are low, high levels of Calcitriol can stimulate resorption |
| Estrogens - decrease bone turn over | glucocorticoids (glucocorticoid induced osteoporosis) |
| Calcitonin - physiologically redundant, pharmacologic doses -> onyl a transient effect of reducing bone resorption | Thyroid hormones - BOTH deposition and resorption. (bone loss can occur in hyperthyroidism) |
| TGF beta adn BMP |
Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]
Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.
[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.
T3 binds to nuclear recetpor --> Exerts effects
T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23
| System | effect |
|---|---|
| CVS | Increase cardiac ouput |
| RS | Maintains respiratory drive |
| GI | increases motility |
| Blood | Incr. 23-DPG - increased oxygen unloading |
| Muscles | Increase speed of muscle contraction |
| Carbs | Increase gluconeogen, glycolysis, sugar absorption |
| lipid | Lipolysis + increased cholesterol turnover |
| Sympathetic NS | Increases expression of beta adrenergic receptors and in heart decreases alpha receptors |
There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease
Low TSH usually means hyperthyroidism except in
High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)
Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32
Common cause of hyperthyroidism
Commoner in women - 30 - 60 years.
Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)
Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.
Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;
Disease follows a relapsing remitting course. Majority have recurrences.
Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia
Patients will usually eventually become hypothyroid.
Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.
Others causes of hyperthyroidism: 
Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.
[!TIP] C --> M: Alphabetical order
[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure
#2022BSQ Q16
Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.
| Carbimazole / methimazole | Propylthiouracil |
|---|---|
| Less severe side effects. Usually first line choice | Usually second line, except T1 of pregnancy, and thyroid storm |
| Blocks 5'-monodeiodinase, which converts peripheral T4 to T3 conversion | |
| Less frequent teratogenic effects | |
| Pruritus, rash, arthritis, urticaria, abnormal taste | Same |
| Agranulocytosis (0.1% incidence) | Same |
| Less risk of hepatic injury | Fulminant hepatic failure |
| ANCA positive vasculitis |
[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.
Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.
Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.
Thyroiditis typically causes a painful goiter.
[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic
Grand Seikos are japanese watches -> chronic ;)
| Hashimoto's | De quervain | Post partum | Drug induced | radiation | Infectious | Silent |
|---|---|---|---|---|---|---|
| chronic autoimmune - months to years | Post viral thyroiditis - days | rare, around 6 months post partum, resolves by 12 months PP | Lithium, interferons | radio-iodine therapy | rare, bacterial infection | |
| Rubbery gland | Painful, warm thyroid | |||||
| Transient hyper, then hypothyroidism | Hyper and then hypothyroidism | |||||
| risk factors: type 1 DM and previous episodes |
Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.
fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.
| Image 1 | Image 2 |
|---|---|
|  |  |
Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)
Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.
Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.
Levothyroxine (aka L thyroxine) is synthetic T4.
Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.
Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin
Lactotroph adenoma - usually very high prolactin levels.
Loss of dopaminergic inhibition
Oestrogen tends to increase prolactin levels.
Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.
Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery
Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.
Dysfunction of islet specific glucokinase can cause one type of MODY.
Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.
[!INFO] Insulin helps to coordinate between different types of fuel used by the body.
Coordination of glucose and lipid metabolism by insulin
- in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
- In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.
Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.
Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]
#2021BSQ-NOV Q07
[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.
| Transporter | Site |
|---|---|
| SGLT-1 | small intestine and renal tubules |
| SGLT-2 | renal tubules |
| GLUT 1,3 | basal glucose uptake 'everywhere' |
| GLUT 2 | beta cell glucose sensor |
| GLUT 4 | insulin mediated glucose uptake in Sk and cardiac muscle, adipocytes |
| GLUT 5 | Fructose transporter |
There are three main types of estrogen: Source
Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.
The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded
If a patients has feature of Chushing's syndrome
bedtime salivary cortisol
24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.
Low dose DST
For bedtime salivary cortisol and UFC, two abnormal tests are required.
If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.
Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)
Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.
Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.
First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.
Because of cyclical variations, testing at two different times is recommended.
ACTH < 5pg/ML = ACTH independent hypercortisolism
ACTH > 20pg/mL = ACTH dependent hypercortisolism.
ACTH dependent Hypercortisolism
A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.
Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.
[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products
Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive
[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion
| Hypothalamic diseases | Pituitary diseases |
|---|---|
| Mass lesions – Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc) | Mass lesions – Pituitary adenomas, other benign tumors, cysts |
| Radiation – For CNS and nasopharyngeal malignancies | Pituitary surgery |
| Infiltrative lesions – Sarcoidosis, Langerhans cell histiocytosis | Pituitary radiation |
| Infections – Tuberculous meningitis | Infiltrative lesions – Hypophysitis, hemochromatosis |
| Other – Traumatic brain injury, stroke | Infection/abscess |
| Infarction – Sheehan syndrome | |
| Apoplexy | |
| Genetic mutations | |
| Empty sella |

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]
| Hormone Type | Site of secretion | Mechanism of action | Receptor Sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| Peptide | Somatotroph cells of Anterior pituitary | Mainly acts on the liver to stimulate IGF-1 production, Acts directly and indirectly on epiphyseal bone | cell membrane receptor (esp. on hepatocytes). Receptor defects cause Laron dwarfism | Pulsatile (10 pulses per day, 90 minutes each -easy to miss in a spot sample) | ||
Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin
Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.
[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity
[!Tip] Mnemonic: GH affects all macromolecules - makes things grow
- Lipids -> increase lipolysis
- Proteins -> Increased protein synthesis
- Glucose -> Promotes insulin resistance
- Electrolytes -> Phosphate, salt and water retention
- Bone -> Epiphyseal bone growth
In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)
Commonest cause in adults: somatotroph adenoma
Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)
Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant
[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]
As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:
[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases
^da9653
[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia
Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.
- Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
- Other effects include
- a lesser stimulation of intestinal phosphate absorption
- direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
- regulation of osteoblast function, and
- permissively allowing PTH-induced osteoclast activation and bone resorption.
- Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.
^83ab8b
The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:
Activated vitamin D levels are elevated in #pregnancy
The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.
| type | Site | Mechanism | Receptor sites | Effects | Transport | Pattern of secretion |
|---|---|---|---|---|---|---|
| peptide | Chief cells of parathyroid gland | ↑ osteoclast bone resorption, ↑ intestinal absorption, ↑ synthesis of D3, ↑ renal rubular resorption, ↑ phosphate excretion | cell membrane |
^0f3395
PTH increases renal phosphate excretion and increases plasma calcium by:
Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.
[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)
Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.
PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source
#2021BSQ-NOV Q08
Indications for therapeutic used:
^070bf7
About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.
| Region | Mechanism | Percentage |
|---|---|---|
| PCT | Passive | 60% |
| TAL | 15% | |
| DCT (site of regulation) | Active | 15% |
| Collecting duct | 0% |
PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source
PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2
[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]
Causes are devided into
malignancy and primary hyperparathyroidism = 90% of cases.

Causes of Severe hypercalcaemia :
Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.
After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate
Not very common
In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures
Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype
Patients have albright phenotype BUT
All biochemistry is normal
[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 depositionTo illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia
Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.
Common in CKD
Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO
Two types of bone formation
Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:
Bone development includes
An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis
Bone deposition and resorption is influenced by both systemic and local factors.
| Systemic | Local |
|---|---|
| + PTH & calcitriol | Prostaglanding |
| GH / IGF-1 | Transforming growth factor (TGF) |
| Glucocorticoids | Bone morphogenic proteins (BMP) |
| thyroid hormones | Cytokines |
| sex hormones | (Levels of local regulators are influenced by mechanical stress, local inflammation etc.) |
More complicated than you might think
| Decrease bone turnover | Increase bone turnover |
|---|---|
| Parathyroid hormones - Intermittent administration -> Stimulates bone formation | PTH - Continous presense --> bone resorption |
| Calcitriol | If Ca and PO4 are low, high levels of Calcitriol can stimulate resorption |
| Estrogens - decrease bone turn over | glucocorticoids (glucocorticoid induced osteoporosis) |
| Calcitonin - physiologically redundant, pharmacologic doses -> onyl a transient effect of reducing bone resorption | Thyroid hormones - BOTH deposition and resorption. (bone loss can occur in hyperthyroidism) |
| TGF beta adn BMP |
Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]
Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.
[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.
T3 binds to nuclear recetpor --> Exerts effects
T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23
| System | effect |
|---|---|
| CVS | Increase cardiac ouput |
| RS | Maintains respiratory drive |
| GI | increases motility |
| Blood | Incr. 23-DPG - increased oxygen unloading |
| Muscles | Increase speed of muscle contraction |
| Carbs | Increase gluconeogen, glycolysis, sugar absorption |
| lipid | Lipolysis + increased cholesterol turnover |
| Sympathetic NS | Increases expression of beta adrenergic receptors and in heart decreases alpha receptors |
There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease
Low TSH usually means hyperthyroidism except in
High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)
Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32
Common cause of hyperthyroidism
Commoner in women - 30 - 60 years.
Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)
Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.
Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;
Disease follows a relapsing remitting course. Majority have recurrences.
Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia
Patients will usually eventually become hypothyroid.
Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.
Others causes of hyperthyroidism: 
Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.
[!TIP] C --> M: Alphabetical order
[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure
#2022BSQ Q16
Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.
| Carbimazole / methimazole | Propylthiouracil |
|---|---|
| Less severe side effects. Usually first line choice | Usually second line, except T1 of pregnancy, and thyroid storm |
| Blocks 5'-monodeiodinase, which converts peripheral T4 to T3 conversion | |
| Less frequent teratogenic effects | |
| Pruritus, rash, arthritis, urticaria, abnormal taste | Same |
| Agranulocytosis (0.1% incidence) | Same |
| Less risk of hepatic injury | Fulminant hepatic failure |
| ANCA positive vasculitis |
[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.
Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.
Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.
Thyroiditis typically causes a painful goiter.
[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic
Grand Seikos are japanese watches -> chronic ;)
| Hashimoto's | De quervain | Post partum | Drug induced | radiation | Infectious | Silent |
|---|---|---|---|---|---|---|
| chronic autoimmune - months to years | Post viral thyroiditis - days | rare, around 6 months post partum, resolves by 12 months PP | Lithium, interferons | radio-iodine therapy | rare, bacterial infection | |
| Rubbery gland | Painful, warm thyroid | |||||
| Transient hyper, then hypothyroidism | Hyper and then hypothyroidism | |||||
| risk factors: type 1 DM and previous episodes |
Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.
fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.
| Image 1 | Image 2 |
|---|---|
|  |  |
Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)
Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.
Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.
Levothyroxine (aka L thyroxine) is synthetic T4.
Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.
Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin
Lactotroph adenoma - usually very high prolactin levels.
Loss of dopaminergic inhibition
Oestrogen tends to increase prolactin levels.
Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.
Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery
Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.
Dysfunction of islet specific glucokinase can cause one type of MODY.
Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.
[!INFO] Insulin helps to coordinate between different types of fuel used by the body.
Coordination of glucose and lipid metabolism by insulin
- in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
- In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.
Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.
Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]
#2021BSQ-NOV Q07
[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.
| Transporter | Site |
|---|---|
| SGLT-1 | small intestine and renal tubules |
| SGLT-2 | renal tubules |
| GLUT 1,3 | basal glucose uptake 'everywhere' |
| GLUT 2 | beta cell glucose sensor |
| GLUT 4 | insulin mediated glucose uptake in Sk and cardiac muscle, adipocytes |
| GLUT 5 | Fructose transporter |
There are three main types of estrogen: Source
Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.
The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded
If a patients has feature of Chushing's syndrome
bedtime salivary cortisol
24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.
Low dose DST
For bedtime salivary cortisol and UFC, two abnormal tests are required.
If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.
Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)
Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.
Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.
First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.
Because of cyclical variations, testing at two different times is recommended.
ACTH < 5pg/ML = ACTH independent hypercortisolism
ACTH > 20pg/mL = ACTH dependent hypercortisolism.
ACTH dependent Hypercortisolism
A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.
Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.
[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products
#2021BSQ-NOV Q31
Leukemoid reaction refers to a white blood cell (WBC) count >50,000/microL from causes other than leukemia. (Usually severe reaction to an infection).
The majority of cells are mature neutrophils, but often accompanied by a prominent left shift.
[!INFO] Left shift
"Left shift" : ill defined term meaning increased band forms, myelocytes and metamyelocytes. -> indicates infection, sepsis of chronic myeloid leukemia.
Myelocytes are neutrophil precursors seen mainly in bone marrow. Metamyelocytes are their descendants, and can be seen in the blood.
Greek "meta" means 'after'.
Band forms are immature neutrophils whose nucleus hasn't yet become segmented and have a C or S shape.
Some Causes:
Clues for cause or neutrophilia:
Spurious neutrophilia / false neurophilia / pseudo neutrophilia:
interferrenace with the particle counter can case false neutrophelia in
#2021BSQ-NOV Q34
Important points:
Causes:
[!INFO] Definition of atrophy
In atrophy, a shell shrinks to a smaller size with reduced function so that it can survive under the new (less conducive) growth conditions imposed by factors listed above.
Atrophic cells are not dead.
Cellular mechanisms:
- Decreased protein synthesis
- Proteolysis - ubiquitin-proteasome pathway which may also be involved in cancer cachexia
- Increased autophagy.
Reprogramming of stem cells to differentiate into a cell type that is more suitable to cope with the new stresses than the original cell type at that location.
I.e results in replacement of one type of mature cell with another type of mature cell.
It is a reversible change;
Example: Squamous metaplasia of respiratory epithelium in smokers.
Vitamin A is essential for normal epithelial differentiation.
Anaplasia: "backward formation" - loss of structural and functional differentiation of cells. A hallmark of malignancy
[!INFO] Dedifferentiation Vs. Lack of differentiation
There may be some technical difference between dedifferentiation and inability to differentiate at all (as seen in cancers of stem cells)
See Robbins (Page 165).
Dysplasia:
==From Wikipedia==
| Agent | Malignancy |
|---|---|
| Viruses | |
| See second table | |
| - | |
| Bacteria | |
| H pylori | Gastric cancer |
| - | |
| Parasites | |
| Schistosoma | SQC of bladder |
| Chlornorchis sinensis | Cholangiocardinoma |
Source
There are 7 known oncogenic viruses
| Virus | Cancer | Major regions affected |
|---|---|---|
| Epstein–Barr virus | • 40% of Hodgkin lymphoma • >95% of endemic Burkitt lymphoma • 10% gastric carcinoma • Most (type II and III) nasopharyngeal carcinoma • Kaposi sarcoma • Other lymphomas | • East Asia • East Africa • Regions of the Americas |
| Hepatitis B virus | • 53% of hepatocellular carcinoma | • Asia • Sub-Saharan Africa • Regions of South America |
| Hepatitis C virus | • 25% of hepatocellular carcinoma • Non-Hodgkin B cell lymphomas | • Regions of Asia, the Americas, North Africa and the Mediterranean |
| Human T-lymphotropic virus 1 | • >99% of adult T cell leukaemia | • Japan • Australia • Regions of Africa, South America and the Middle East |
| Human papillomavirus | • >95% of cervical carcinoma • 70% of oropharyngeal carcinoma • Other anogenital carcinomas | • Central America • South America • Sub-Saharan Africa • Regions of Asia |
| Kaposi sarcoma-associated herpesvirus (AKA HHV-8) | • >99% of Kaposi sarcoma • >99% of primary effusion lymphoma | • Regions of Europe and sub-Saharan Africa |
| Merkel cell polyomavirus | • 80% of Merkel cell carcinoma | • North America • Australia • Europe |
Gatric cancer can be
H pylori infection is associated with several types of gastric cancer.
Treatment of H pylori infection reduces cancer risk.
The exact mechanism is not known but there are several theories.
Types of cancer associated with H. pylori:
(AKA TNF-alpha, AKA TNF-α, aka cachexin)
Endothelial cell contraction occurs rapidly after binding of histamine, bradykinin, leukotrienes, and many other mediators to specific receptors, and is usually short-lived (15 to 30 minutes). A slower and more prolonged retraction of endothelial cells, resulting from changes in the cytoskeleton, may be induced by cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1).
Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in
- Hashimoto thyroiditis
- multinodular hypoplasia
- lymphocytic thyroidis
- Source
[!TIP] Watery diarrhoea
#2021BSQ-NOV Q33
| +ve APR | -ve APR |
|---|---|
| Fibrinogen(large effect on ESR) | Albumin |
| Haptoglobin | Transferrin |
| Alpha 1 antitrypsin - protease inhibitor | Antithrombin |
| Hepcidin - hormone controlling iron absorption | retinol binding protein |
| procalcitonin | |
| [[Anaemia#Iron metabolism and iron studies|Ferritin]] | |
| Serum amyloid A: Rises x1000 during acute phase. Role unkown. Maybe cytokines Source | |
"For F*cks Sake, Protect Harry's Ass Hole " - +ve acute phase reactancts.